Liquid and low melting coatings for stents

ABSTRACT

A method for forming liquid coatings for medical devices such as stents and angioplasty balloons is provided. The liquid coatings can be made from biodegradable materials in liquid, low melting solid, or wax forms, which preferably degrade in the body without producing potentially harmful fragments. The liquid coatings may also contain biologically active components, which are released from the coatings through diffusion from the coatings and the degradation of the coatings.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of co-pending U.S. patent applicationSer. No. 10/027,374, filed Dec. 21, 2001, entitled “Liquid And LowMelting Coatings For Stents”, which is a continuation-in-part ofco-pending U.S. patent application Ser. No. 09/991,235, filed Oct. 22,2001, entitled “Stent Coatings Containing HMG-CoA Reductase Inhibitors,”both of which are hereby incorporated herein by reference in theirentirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention generally relates to coated stents, compositionsfor coating stents, methods of making coated stents, and methods ofusing coated stents.

2. Description of the Related Art

Stents are often used in the treatment of atherosclerosis, a disease ofthe vascular system in which arteries become partially, and sometimescompletely, occluded with substances that may include lipids,cholesterol, calcium, and various types of cells, such as smooth musclecells and platelets. Atherosclerosis is a very common disease which canbe fatal, and methods of preventing the accumulation of occludingcompounds in arteries are being investigated.

Percutaneous transluminal coronary angioplasty (PTCA) is a commonly usedprocedure to break up and/or remove already formed deposits alongarterial walls. PTCA can also be used to treat vascular occlusions notassociated with atherosclerosis. During PTCA, a catheter is threadedthrough a patient's arteries until the occluded area to be treated isreached. A balloon attached to the end of the catheter is then inflatedat the occluded site. The expanded balloon breaks up the mass ofoccluding substances, resulting in a more open arterial lumen. However,there is a risk that the artery may re-close within a period of from oneday to approximately six months after the procedure. This re-closure isknown as restenosis. Accordingly, a balloon-only angioplasty procedureoften does not result in a permanently reopened artery. To preventrestenosis, scaffolding devices called stents are often deployed in thelumen of the artery as a structural support to maintain the lumen in anopen state. Unlike the balloon and the catheter used in an angioplastyprocedure, the stent remains in the artery as a permanent prosthesis.Although technically feasible, removal of the stent from the artery isgenerally avoided.

Stents are typically elongated structures used to keep open lumens(i.e., openings) found in various parts of the body. Stents are usuallyimplanted by coupling them in a compressed state to a catheter which isrouted through the body to the site of stent deployment. The stent canbe expanded to a size, which enables it to keep the lumen open by directcontact with the wall of the lumen once it is positioned at the desiredsite.

Blood vessels are common sites of stent deployment. Vascular stents arefrequently used in blood vessels to open the vessel and provide improvedblood flow. The stents are typically hollow, cylindrical structures madefrom struts or interconnected filaments. Vascular stents can becollapsed to a reduced diameter so that the stent can be guided througha patient's arteries or veins to reach the site of deployment. Stentsare typically either coupled to the outside of the balloon for expansionby direct contact with the expanding balloon or are self-expanding uponremoval of a restraint such as a wire or sleeve maintaining the stent inits collapsed state.

The stent is allowed to expand at the desired site to a diameter largeenough to keep the blood vessel open. Vascular stents are often made ofmetal to provide the strength necessary to support the occluded arterialwalls. Two of the preferred metals are Nitinol alloys of nickel andtitanium, and stainless steel. Other materials that can be used instents are ceramics, polymers, and plastics. Stents may be coated with asubstance, such as a biodegradable or biostable polymer, to improve thebiocompatibility of the stent, making it less likely to cause anallergic or other immunological response in a patient. A coatingsubstance may also add to the strength of the stent. Some known coatingsubstances include organic acids, their derivatives, and syntheticpolymers that are either biodegradable or biostable. Biodegradablecoating substances can degrade in the body; biostable coating substancesdo not. A problem with known biodegradable and biostable stent coatingsis that both types of coatings are susceptible to breaking and crackingduring the temperature changes and expansion/contraction cyclesexperienced during stent fabrication and use.

Stents located within a lumen in the body may not always prevent partialor complete restenosis. In particular, stents do not always prevent there-narrowing of an artery following PTCA. In fact, the introduction andpresence of the stent itself in the artery or vein can create regions oftrauma such as, e.g., tears in the inner lining of the artery, calledthe endothelium. It is believed that such trauma can trigger migrationof vascular smooth muscle cells, which are usually separated from thearterial lumen by the endothelium, into the arterial lumen, where theyproliferate to create a mass of cells, which may in a matter of days orweeks re-occlude the artery. The resulting re-occlusion of the artery,which is sometimes seen after PTCA, is an example of restenosis. Coatinga stent with a substance to make the surface of the stent smoother andto minimize damage to the endothelium has been one method used to createstents that are less likely to contribute to restenosis.

Currently, drug therapy for restenosis primarily consists of thesystemic administration of drugs. However, delivering drugs in thismanner may result in undesirable side effects in other areas of the bodyunrelated to the vascular occlusion. Also a drug which is deliveredsystemically is less effective in achieving the desired effect in thelocal area of the body in which it is actually needed. For example, ananti-restenosis drug delivered systemically may be sequestered ormetabolized by other parts of the body, resulting in only a small amountof the drug reaching the local area where it is needed.

Stents with bioactive compounds or drugs in or on their coatings havebeen proposed. Typically, such coatings comprise a polymeric carrier andan active drug or anti-restenosis agent. One class of drugs that can beused in stent coatings is restenosis inhibitors. Although a number ofdrugs have been shown to be candidates to reduce restenosis rates incardiovascular stents, there remains a need for coatings which can beshown to actually release the restenosis inhibiting compounds in theiractive forms. Further, there is a need for carriers for use in coatedstents, which can carry drugs and release them in a sufficientconcentration to produce the desired effect. In particular, there is aneed for such stents, which can inhibit restenosis.

One problem with the biodegradable carriers currently proposed forincorporation in coatings for stents and angioplasty balloons is that,because they are invariably solids at body temperature and below, theymay degrade into fragments which can be sharp. These fragments candamage the endothelium, and thus contribute to restenosis. There is thusa need for stents (and other medical devices such as angioplastyballoons) having biodegradable coatings, and particularly carriers usedin such coatings, that do not break down into harmful fragments.Furthermore, there is a need for such coatings which contain bioactivecompounds that can be released a carrier to provide localized drugdelivery at the site of the stent. Coatings which can release a highdose of bioactive compound quickly, and thus prevent or treat anunhealthy condition as quickly as possible, are also desired.

SUMMARY OF INVENTION

Broadly, the invention relates to coated stents, methods of makingcoated stents and methods of using coated stents. At least certainembodiments of the invention provide a coated stent comprising a stenthaving a coating composition that includes a biologically activecomponent and a biodegradable, low-melting carrier component.Accordingly, in one embodiment, the invention provides a stent having acoating composition comprising a biologically active component and abiodegradable carrier having a melting point of about 50° C. or less,more preferably about 45° C. or less. More particularly, thebiodegradable carrier component has a melting point of from about 10° C.to about 50° C., more preferably from about 35° C. to about 45° C. Inother specific embodiments, the invention provides a coated stentcomprising a stent and a coating composition that includes a bioactivecomponent and a biodegradable liquid carrier component having aviscosity of from about 0.1 to about 15,000 centipoise, and morepreferably from about 0.1 to 5000 centipoise (cP). In yet anotherspecific embodiment, the invention includes a stent with a coatingcomposition that is in a solid state at room temperature (22° C.)outside a human body and that melts to form a liquid inside a humanbody.

Coating compositions according to the present invention are preferablyhydrophobic. More preferably, the biodegradable carrier component of thecoating composition is hydrophobic. The carrier component is alsopreferably biocompatible. The biodegradable carrier may comprise apolymer. When the biodegradable carrier comprises a polymer, the polymerpreferably has a molecular weight of 50,000 or less, more preferably5000 or less, and even more preferably 2000 or less. The carrier polymermay be selected from the group consisting of polyhydroxy acids,polyanhydrides, polyphosphazenes, biodegradable polyamides, polyalkyleneoxalates, polyorthoesters, polyphosphoesters, polyorthocarbonates, andblends or copolymers thereof. Alternatively, and more preferably, thecarrier comprises a non-polymer and is preferably entirelynon-polymeric. For example, the carrier component may comprise vitamin Eor its derivatives, oleic acid, peanut oil, or cottonseed oil, alone orin combination.

Preferably, the biologically active component is capable of inhibitingrestenosis. The biologically active component may be selected from thegroup consisting of paclitaxel, actinomycin D, rapamycin, cerivastatinand other statin drugs. Preferably, those components are released from astent in an amount effective to inhibit restenosis.

In certain specific embodiments, the coated stent comprises a stent anda coating composition comprising a biodegradable or biostable carriercomponent. Where the biodegradable or biostable carrier is itself abiologically active component, the carrier should have a melting pointof about 50° C. or less.

In another aspect, the invention can include a method of coating astent. A specific embodiment of the method includes providing a coatingcomposition that includes a biologically active component and abiodegradable carrier component that has a melting point of about 50° C.or less, and applying the coating composition to the stent. In anotherspecific embodiment, the invention includes a method that comprisesproviding a coating composition that includes a biologically activecomponent and a biodegradable carrier component which has a viscosity offrom about 0.1 to about 15,000 cP, and applying the coating compositionto the stent.

In another embodiment, a method of coating a stent may compriseexpanding the stent to an expanded position before applying the coatingcomposition to the stent. The coating composition may be applied to thestent in any number of ways, e.g., by spraying the coating compositiononto the stent, by immersing the stent in the coating composition, or bypainting the stent with the coating composition. Other coating methodssuch as electrodeposition can also be used. In one embodiment, excesscoating composition is allowed to drain from the stent. In anotherembodiment, the stent is dried after the coating composition is appliedto the stent to provide a solid coating composition. In preferredembodiments, the coating is applied with the bioactive componentdissolved in the carrier component. In alternative embodiments, thecarrier component may be applied to the stent and the bioactivecomponent applied to the carrier. In another alternative embodiment, thebioactive component may be applied to the stent and the carriercomponent applied to the bioactive component.

In one or more specific embodiments, the invention can include atreatment method, comprising inserting a coated stent into a body lumenof a person, the coated stent comprising a stent and a coatingcomposition comprising a biodegradable carrier component and abiologically active component, the biodegradable carrier componenthaving a melting point of about 50° C. or less, more preferably 45° C.or less. In other specific embodiments, the coated stent provides astent and a coating composition comprising a biodegradable carriercomponent and a biologically active component, the carrier componenthaving a viscosity of from about 0.1 to about 15000 cP, or from about0.1 to about 5000 cP. In yet another specific embodiment, the coatedstent comprises a stent and a coating composition that comprises abiodegradable carrier component and a biologically active component, andthe coating composition (or at least the carrier component thereof) isin a solid state outside of a human body and a liquid inside of a humanbody.

In another aspect, the invention can include a treatment method,comprising attaching a stent to a catheter, spraying the catheter andthe stent with a coating composition comprising a biodegradable carriercomponent, and a biologically active component having a melting point ofabout 50° C. or less, and inserting the coated stent into a body lumenof a person.

In another aspect, the invention can include a coated stent, comprisinga stent and a coating composition comprising a biologically activecomponent and a biodegradable carrier component which may have a meltingpoint of about 50° C. or less, and a catheter which can be coupled tothe coated stent to form a treatment assembly.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-section of an artery experiencing restenosis in thepresence of an uncoated stent.

FIG. 2 is a cross-section of an artery containing a coated stent.

FIG. 3 is a stent.

FIG. 4 is a UV-VIS spectra of cerivastatin released from a stentcoating.

FIG. 5 is a release profile of cerivastatin released from a stentcoating.

FIG. 6 is a release profile of cerivastatin released from a stentcoating.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

An exemplary artery 10 experiencing restenosis is shown in FIG. 1. Theendothelium 12 normally serves as a solid barrier between the layer ofsmooth muscle cells 14 and the arterial lumen 20. Small tears 16 in theendothelium 12 can expose smooth muscle cells 14, which can then migrateinto the arterial lumen 20 and hyperproliferate into a mass 18 which canpartially or completely occlude the lumen 20 even though an uncoatedstent 21 is placed, during a procedure such as angioplasty, in theartery 10 to keep the arterial lumen 20 open.

An artery 10 containing a coated stent 22 prepared according to anembodiment herein is shown in FIG. 2. The stent has a coating 24containing a carrier and a bioactive compound which inhibits restenosis.By using a stent having this coating 24, the tears 16 shown in FIG. 1 inthe endothelium 12 may be reduced or eliminated. Additionally, the mass18 created by hyperproliferation of smooth muscle cells 14, as shown inFIG. 1, is eliminated or substantially reduced.

FIG. 3 illustrates a stent 21 suitable for use in connection with thepresent invention. In one embodiment, the stent 21 comprises a hollowreticulated tube. The tubular body of stent 21 is defined by a number offilaments or struts 25 which surround open cells 26. The stent 21comprises an inner surface 27 facing the interior of the stent and anouter surface 28 facing the exterior. In a preferred embodiment, acoating (not shown) covers both the inner surface 27 and the outersurface 28. In alternative embodiments, the coating may cover only theinner surface, only the outer surface, or portions of one or both of theinner and outer surfaces. The coating may aggregate at the intersectionof filaments 25. In a preferred embodiment, the coated stent 22 is madeout of a metal or metal alloy, such as titanium, tantalum, stainlesssteel, or nitinol.

At least certain embodiments of the invention include a coated stentcomprising a stent and a coating composition that includes abiologically active component and a biodegradable carrier componenthaving a melting point of about 50° C. or less. Preferably, thebiodegradable component has a melting point of from about 10° C. toabout 50° C., and most preferably, from about 35° C. to about 45° C. Inother specific embodiments, the invention provides a coated stentcomprising a stent and a coating composition comprising a bioactivecomponent and a liquid biodegradable carrier component that has aviscosity of from about 0.1 to about 15000 cP, and more preferably, fromabout 0.1 to about 5000 cP. In yet another specific embodiment, theinvention includes a stent with a coating composition that is in a solidstate at room temperature (22° C.) a human body and that melts to form aliquid inside a human body at body temperature (37° C.).

In a preferred embodiment, the coating 24 (FIG. 2) is made by mixingtogether a biologically active component (e.g., a restenosis-inhibitingagent) and a carrier in which the biologically active component issoluble. In a particularly preferred embodiment, the carrier is a liquidoil that adheres to the inner and outer surfaces 27, 28 of the stent 21(FIG. 3). In other embodiments, the carrier comprises a low-meltingpolymer dissolved in a solvent, which is then removed by, e.g., drying,to yield a solid coating composition comprising the polymer andbioactive component, which may comprise a restenosis inhibiting agentsuch as an HMG-CoA reductase inhibitor.

As discussed, the coated stent of this invention includes a stent and acoating composition. The coating composition described herein ispreferably a blend of a biologically active component and abiodegradable low-melting carrier component. The terms “biologicallyactive” and “bioactive” refer to a substance having an effect on aliving organism. See generally, Merriam Webster's Collegiate Dictionary(10^(th) ed., 2001). Preferably, the effect of a bioactive compound istherapeutic in nature. The term “biodegradable” as used herein refers toa substance that breaks down into non-toxic byproducts which areeliminated by the body. The term “low-melting” refers to a compositionhaving a melting point of 50° C. or less. Carrier compositions havingmelting points below 50° C. allow liquid-form delivery of a bioactivecomponent to a body lumen either with no heat at all (because thecomposition is a liquid at body temperature) or with relatively benignheating without denaturing or other harm to the patient. In anotherembodiment, the coating composition is a blend of a bioactive componentand a low-melting carrier comprising a biodegradable component, abiostable component, or both. In yet another embodiment, the coatingcomposition is a liquid carrier that is biodegradable or biostable.

In addition to stents, examples of other medical devices that can becoated in accordance with aspects of the inventions disclosed hereininclude catheters, heart valves, pacemaker leads, annuloplasty rings andother medical implants. In other specific embodiments, coatedangioplasty balloons and other coated medical devices can also compriseone of the coating compositions disclosed herein. However, stents arepreferred. The coating composition may be applied to the stent (or othermedical device) by any number of ways, e.g., by spraying the coatingcomposition onto the stent, by immersing the stent in the coatingcomposition, or by painting the stent with the coating composition.Preferably, a stent is coated in its expanded (i.e., enlarged diameter)form so that a sufficient amount of the coating composition will beapplied to coat the entire surface of the expanded stent. When the stentis immersed in the coating composition, the excess coating compositionon the surface of the stent may be removed, such as by brushing off theexcess coating composition with a paint brush. In each of these coatingapplications, preferably both the outer and inner surfaces of the stentare coated.

An important aspect of the coating compositions of the present inventionis the melting point of the biodegradable component. Preferably, thebiodegradable component has a melting point of 50° C. or less, and morepreferably from about 35° C. to about 45° C. The term “melting point”refers generally to the temperature at which a pure substance's crystalsare in equilibrium with the liquid phase at atmospheric pressure. Seegenerally, Hawley's Condensed Chemical Dictionary (11^(th) Ed., 1987).Whenever melting points are discussed or referred to herein inquantitative terms, the melting point is measured according todifferential scanning calorimetry or other standard methods shown inanalytical or organic chemistry textbooks (see, e.g., AnalyticalChemistry Handbook, Section 15, J. A. Dean, McGraw-Hill, Inc., 1995).

Another important aspect of certain embodiments of the invention is thebiodegradable carrier component. In a preferred embodiment of thisinvention, the carrier component of the coating composition is orincludes one or more non-polymeric, biodegradable compounds ormaterials, which either contain no polymers at all or containessentially no polymers. For example, the carrier component shouldcontain less than 50% by weight polymer, preferably less than 25 wt %polymer, more preferably less than 10 wt %, and most preferably lessthan 1 wt % polymer material. The biodegradable carrier component ispreferably homogeneous (single phase) and may comprise a mixture ofcomponents that exist together as a solution, but which mayalternatively be a multiple phase blend. Examples of preferrednon-polymeric biodegradable carriers include liquid oleic acid, vitaminE, peanut oil, and cottonseed oil, which are liquids that are bothhydrophobic and biocompatible. As used herein, the term “biocompatible”means any material that is not harmful to and preferably does not causean immunological response in a living body, e.g., a living human being.As used herein, the term “polymer” means a macromolecule havingrecurring carbon-containing units, formed by a human-initiated orcontrolled polymerization reaction using monomers as reactants. The term“non-polymer” means any material that is not a polymer, includingcarbon-based materials such as naturally occurring oils.

Although non-polymeric carriers are preferred, the biodegradable carriermay also comprise a polymer. In one embodiment, the carrier comprisesone or more biodegradable polymers, in which case it preferably consistsessentially of one or more biodegradable polymers. In one embodiment,these polymers include low-melting polyhydroxy acids. Examples ofpolyhydroxy acids suitable for use in the present invention includepoly-L-lactic acids, poly-DL-lactic acids, polyglycolic acids,polylactides including homopolymers and copolymers of lactides(including lactides made from all stereoisomers of lactic acids, such asD-,1-lactic acid and meso lactic acid), polylactones, polycaprolactones,polyglycolides, polypara-dioxanone, poly1,4-dioxepan-2-one,poly1,5-dioxepan-2-one, poly6,6-dimethyl-1,4-dioxan-2-one,polyhydroxyvalerate, polyhydroxybutyrate, polytrimethylene carbonate,and blends of the foregoing, it being understood that the polymers havemolecular weights such that their melting points are 50° C. or less.Polycaprolactones suitable for use in the present invention includelow-melting, low molecular weight moieties of polycaprolactones such aspoly ε-caprolactone), polyvalerolactones such as polyδ-valerolactone),and polybutyrolactones such as poly(λ-butyrolactone). Otherbiodegradable polymers that can be used in carriers of the presentinvention are low-melting, low molecular weight moieties ofpolyanhydrides, polyphosphazenes, biodegradable polyamides such assynthetic polypeptides such as polylysine and polyaspartic acid,polyalkylene oxalates, polyorthoesters, polyphosphoesters, andpolyorthocarbonates. The biodegradable polymers may be linear orbranched. The biodegradable polymers may be homopolymers or terpolymersincluding random copolymers or block copolymers. Copolymers and blendsof any of the listed polymers may be used. Polymer names above that areidentical except for the presence or absence of parentheses representthe same polymers.

The structure and molecular weight of polymers used as biodegradablecarriers in the present invention can be controlled during theirsynthesis in order to produce polymers that are liquid either at ambienttemperatures (from 20° C. to 30° C.) or room temperature (about 22° C)or that have low melting points. In a preferred embodiment, the meltingpoint of the biodegradable polymers is above 30° C. but below typicalhuman body temperature, i.e., 37° C. It is contemplated that a polymerwith a melting point above 37° C. will not turn to liquid while orshortly after the stent is being inserted into the body. A biodegradablepolymer having the desired melting point is preferably a polymer havinga low molecular weight, e.g., a polymer having a molecular weight ofless than about 2000, and preferably less than about 1000. Highmolecular weight polymers which are liquid at room temperature may alsobe used, however, such as certain polyorthoesters described in U.S. Pat.No. 4,913,903, which is hereby incorporated by reference herein in itsentirety. Methods for making specific biodegradable polymers having themelting points, viscosities, and/or molecular weights described hereinare known and will not be described herein. Conventional polymers havingthe desired melting points or viscosities can be obtained fromSigma-Aldrich. Examples of such polymers are shown in Table 1. TABLE 1Commercially available polymers (Sigma-Aldrich, St. Louis, MO) that canbe used in coating applications Physical Molecular Melting appearanceweight point/softening at ambient Substance Name (Dalton) point (° C.)temperature Polycaprolactone diol 2000 50 Solid Polycaprolactone diol530 35 Paste/waxy solid Polycaprolactone triol 900 30 Paste/waxy solidPolycaprolactone triol 300 10 Liquid

As used herein, the terms “liquid” and “solid” are defined according totheir broadest recognized definitions. Unless stated otherwise, amaterial is determined to be a “liquid” or “solid” at room temperature,i.e., 22° C. The term “liquid,” when referring to carriers and coatingcompositions according to the present invention, includes a fluid (aswater) that has no independent shape but has a definite volume, does notexpand indefinitely and is only slightly compressible. The term “liquid”also includes any amorphous (e.g., noncrystalline) form of matterintermediate between gases and solids in which the molecules are muchmore highly concentrated than in gases but much less concentrated thanin solids. See, generally, Hawley's Condensed Chemical Dictionary,(11^(th) Ed., 1987). As discussed in further detail below, an amorphousliquid having a high viscosity can be used to advantage in compositionsaccording to the present invention. The term “solid,” when referring tocarriers and coating compositions, includes a substance that does notflow perceptibly under moderate stress, has a definite capacity forresisting forces (e.g., compression or tension) which tend to deform it,and, under ordinary conditions, retains a definite size and shape. Seegenerally, Merriam Webster's Collegiate Dictionary (10^(th) ed., 2001).

The coating composition, including the bioactive component and thecarrier, should be non-fragmentary. That is, the coating compositionpreferably does not break down into solid, potentially harmful fragmentswhen the coated stent is in the body. In certain embodiments, thebiodegradable carrier is a liquid when it is part of the coatingcomposition residing on the stent outside the body. This liquid isincapable of breaking down into solid, potentially harmful fragments. Inother embodiments, the biodegradable carrier is a solid that preferablybecomes a liquid when introduced to the body (or shortly thereafter).For example, the carrier can be a solid at typical ambient temperatures(i.e., from 20° C. to 30° C.), and is preferably a solid at about 22°C., i.e., room temperature. It should, however, become a liquid at thetemperature of a human body, which is approximately 37° C. In otherwords, the biodegradable component may be a solid outside a human bodyand a liquid inside a human body, so that it melts to form a liquid wheninside the body. It is also contemplated that one skilled in the art mayblend a biodegradable compound which is solid at typical ambienttemperatures (or room temperature) with other components to form acarrier which can be either a liquid at ambient temperatures (or roomtemperature) or a liquid at the temperature of a human body.

In yet a further embodiment of the present invention the coatingcomposition comprises a nonpolymeric compound that is a solid at roomtemperature but becomes a liquid at or near body temperature. Inparticular, the coating composition comprises low molecular weight waxesand derivatives having a melting point at between about 30° C. and 40°C., more particularly from about 35° C. to 40° C. and more particularlyabout 36° C. to about 38° C. In preferred embodiments, the low meltingsolid is applied to the stent by heating the solid to above its meltingpoint, then sprayed, painted, dipped, molded, or otherwise applied tothe stent as a liquid and allowing the liquid to resolidify upon coolingat ambient temperatures.

In another embodiment, two or more types of biodegradable compounds(polymers or non-polymers) may be blended together to obtain a liquidcarrier for use in the coating composition. The biodegradable compoundscan be liquids before they are mixed together, e.g., forming ahomogeneous solution, mixture, or suspension. Alternatively, some of thebiodegradable compounds may be solids before they are mixed with otherliquid biodegradable compounds. The solid biodegradable compoundspreferably dissolve when they are mixed with the liquid biodegradablecompounds, resulting in a liquid carrier composition containing thedifferent biodegradable compounds. In another embodiment, thebiodegradable carrier component of the coating composition is a solid,which dissolves when mixed with the biologically active component andany other components included in the coating composition.

In certain specific embodiments, an important aspect of thebiodegradable carrier component is its viscosity. Generally, viscosityis a term that refers to thickness or resistance to flow. Inquantitative terms, the biodegradable component should have a viscosityof from about 0.1 to about 15000 cP. A person skilled in the polymerchemistry art can use Brookfield viscometer to measure viscosity ofvariety of fluids. Whenever viscosity is discussed herein inquantitative terms, the term “viscosity” is defined according to an ASTMmethod describing viscosity measurement can be found in Test MethodD2983-87 entitled “Standard Test Method for Low-Temperature Viscosity ofAutomotive Fluid Lubricants Measured by Brookfield Viscometer.”

Preferably, liquid stent coatings, such as those made from the materialsdescribed herein, have sufficient viscosity to withstand blood and otherbody fluids flowing against them without being washed off a stent, bothduring the insertion of the stent into the body and after theimplantation of the stent at the desired site. Accordingly, in apreferred embodiment, the biodegradable carrier is a highly viscousliquid, e.g., an amorphous or even a “slimy” material that forms aliquid coating on the stent. A viscosity of from about 0.2 to about 200cP is preferred. Preferably, the viscosity of the biodegradable carrierresults in a coating that is less likely to be removed from the stent bythe shear forces created by blood flow past the stent than a coatingincluding a biodegradable carrier having a lower viscosity. The variousviscosities discussed herein are measured at 20° C.

Biodegradable carriers and coating compositions according to the presentinvention are preferably hydrophobic so that the coating composition isnot immediately dissolved and washed off the stent in the aqueousenvironment of the body. Hydrophilic and water-soluble biodegradablecarriers and coating compositions may in some cases be used, but theyare less preferred because of their tendency to be dissolved and washedoff the stent more quickly than hydrophobic and water-insolublebiodegradable carriers and coating compositions. The term “hydrophobic”is defined according to its broadest recognized definition, and includesbeing antagonistic to water, and incapable of dissolving, or havinglimited solubility, in water. See generally, Hawley's Condensed ChemicalDictionary (11^(th) Ed., 1987).

An important aspect of certain embodiments of the invention is thebiologically active component. One or more biologically activecomponents are included in the coating composition; preferably beforethe coating composition is applied to a stent. It is, however,contemplated that the biologically active component may in certain casesbe combined with the carrier to form the coating composition after thebiodegradable component is applied to the stent. As discussed above, thecoated stent may be used to deliver a bioactive material to a localizedarea in a body. Preferably, the biologically active component is onethat inhibits restenosis and/or prevents smooth muscle cellproliferation. Preferred examples of biologically active components arecomponents that inhibit cell growth by affecting one of the stepsinvolved in the cell cycle. Preferred components that affect the cellcycle are anticancer agents such as paclitaxel, immunosuppressantcompounds such as rapamycin, antibiotics such as actinomycin D, andHMG-CoA reductase inhibitors such as cerivastatin. Other bioactivecomponents forming part of the coating composition can include compoundssuch as antithrombin agents such as heparin and hirudin, calcium channelblockers such as colchicine, and compounds that promoteendothelialization such as nitric oxide or nicotine. In a preferredembodiment, the biologically active component is hydrophobic and iseasily dissolved in the biodegradable carrier to form a hydrophobicliquid coating composition. It is particularly preferred that thehydrophobic biologically active component(s) have a low molecularweight, i.e., a molecular weight below 2000, and more preferably below1000, which can be used to administer a localized treatment in the areaof stent deployment. The treatment may be for a condition such asrestenosis.

In embodiments in which a biologically active component is included inthe coating composition, the biologically active component itself may bea liquid. For example, vitamin E and nicotine (free base) are liquid atambient temperatures (see Table 2) and may potentially have ananti-restenosis therapeutic effect. Preferably, the liquid biologicallyactive component is biodegradable. In certain embodiments, the coatingcomposition may consist essentially of the biologically activecomponent, without a separate carrier component. In certain embodiments,the coating composition may consist of the biologically activecomponent. TABLE 2 Bioactive compounds that are liquid or low meltingsolids (Sigma-Aldrich 2000 catalog) Physical Molecular appearance weightMolecular at ambient Substance Name (Dalton) formula temperature VitaminE 431 C₂₉H₅₀O₂ Liquid Vitamin E acetate 473 C₃₁H₅₂O₃ Liquid Nicotine 162C₁₀H₁₄N₂ Liquid Nicotine Hemisulfate Salt 212 C₁₀H₁₄N₂• Liquid ½H₂SO₄

As discussed above, the coating composition comprises a bioactivecomponent and a biodegradable carrier component. Preferably, the coatingcomposition comprises from 0.1% to 100% by weight of a biologicallyactive component and from 1% to 99% by weight of a biodegradable carriercomponent. More preferably, the coating composition comprises from 0.1%to 50% by weight of a biologically active component and from 50% to99.9% by weight of a biodegradable carrier component. The coatingcomposition can be prepared in a number of ways including by simplymixing the bioactive component and the carrier component together toform a mixture, e.g., a solution or suspension. Alternatively, thebioactive component and the carrier component together are mixed in asuitable solvent, the coating is applied to the stent, and the solventis removed. Preferably the coating composition is applied to the stentin its expanded state.

Where a biologically active component is included in or on the coatingcomposition, the biologically active component may compromise an HMG-CoAreductase inhibitor. In certain specific embodiments, a coated stent cancomprise a stent and a coating composition comprising a substantiallyunreacted HMG-CoA reductase inhibitor and a carrier. The carrier in thecoating composition may be either biodegradable or biostable.

In one embodiment, the coating composition comprises a blend of anHMG-CoA reductase inhibitor and a liquid oil, which may be nonpolymericor polymeric, capable of adhering to the inner surface 27 and/or theouter surface 28 of a stent 21 as shown in FIG. 3. In anotherembodiment, the coating composition comprises a blend of an HMG-CoAreductase inhibitor and a polymer. These two ingredients are preferablyblended, e.g., mixed thoroughly but not chemically reacted to anysubstantial degree. Preferably the HMG-CoA reductase inhibitor issubstantially unreacted. The term “substantially unreacted,” whenreferring to the HMG-CoA reductase inhibitor, means that the inhibitordoes not chemically react with the oil, the polymer or any othercomponent of the coating or the stent, to any degree that substantiallyreduces its biological activity, such as inhibiting restenosis, e.g., byinhibiting the proliferation of smooth muscle cells 14. Where thecoating comprises a polymer, the reductase inhibitor is preferablyphysically bound to the polymer and/or to the stent, but not chemicallybound to any significant degree. In a preferred embodiment, the carrier,whether liquid or solid, polymeric or nonpolymeric, is incapable ofreacting chemically with the inhibitor, i.e., is totally non-reactive(inert) with respect to the inhibitor.

The biologically active component, e.g., an HMG-CoA reductase inhibitor,should remain active even after being blended with the carrier to formthe coating composition and after the coating composition is applied tothe stent and the stent is sterilized. Further, the bioactive componentpreferably remains active when the coated stent is introduced into thebody of a patient, e.g., through a lumen, remains active when it isreleased from the stent into the local environment. An “effectiveamount” of the HMG-CoA reductase inhibitor (or other bioactivecomponent) means an amount that is sufficient when delivered to alocalized area in the body lumen of a patient to inhibit theproliferation of smooth muscle cells in a body lumen of a patient. An“effective amount” of the biodegradable carrier means an amount of thecarrier sufficient to dissolve or suspend an effective amount of thebioactive component and to substantially coat the portion of the stentthat is desired to be coated, preferably the entire stent. Preferably,the carrier has no functional groups that react with the bioactivecomponent, e.g., an HMG-CoA reductase inhibitor, under the conditions offorming the blend with the HMG-CoA reductase inhibitor.

In one or more embodiments, the carrier can be liquid at roomtemperature or it can be solid at room temperature but have a lowmelting point. It can alternatively or also have a specified highviscosity. In a specific embodiment, an HMG-CoA reductase inhibitor isprovided in a nonpolymeric carrier. In another embodiment, the HMG-CoAreductase inhibitor is provided in a polymeric carrier, and the HMG-CoAreductase inhibitor may be physically bound to the polymer, chemicallybound to the polymer, or both. The coating composition can be a liquidsolution at room temperature, comprising the HMG-CoA reductase inhibitorand the polymeric or nonpolymeric carrier, and which may additionallycomprise a solvent, which later may be removed, e.g., by drying.Alternatively, the coating composition may be a solid at roomtemperature and a liquid at body temperature.

In certain specific embodiments, the coating composition preferablyincludes an effective amount of an HMG-CoA reductase inhibitor. Moreparticularly, the coating composition preferably includes an amount ofan HMG-CoA reductase inhibitor that is sufficient to be therapeuticallyeffective for inhibiting regrowth of plaque or inhibiting restenosis. Inone embodiment, the coating composition may comprise from about 1 wt %to about 50 wt % HMG-CoA reductase inhibitor, based on the total weightof the coating composition. Preferably, the coating compositioncomprises from about 5 wt % to about 30 wt % HMG-CoA reductaseinhibitor. More preferably, the coating composition includes from about10 wt % to about 20 wt % HMG-CoA reductase inhibitor. Any HMG-CoAreductase inhibitor may be used, but the HMG-CoA reductase inhibitor ispreferably hydrophobic and selected from the group consisting ofcerivastatin, simvastatin, lovastatin, atorvastatin, and pravastatin.More preferably, the HMG-CoA reductase inhibitor is cerivastatin.

In one embodiment, the carrier of the coating composition is polymeric.In one embodiment, the coating composition comprises an effective amountof a polymer, e.g., an amount sufficient to both dissolve or suspend theHMG-CoA reductase inhibitor and coat a desired portion of the stent. Thepolymer is preferably non-reactive with the HMG-CoA reductase inhibitor,i.e., no chemical reaction occurs when the two are mixed. The polymermay be a polymer having no functional groups, or may be one havingfunctional groups, but none that are reactive with the HMG-CoA reductaseinhibitor. To provide coatings in which HMG-CoA reductase inhibitors arephysically rather than chemically bound to the polymers in the coatings,HMG-CoA reductase inhibitors and carriers are chosen such that they willnot have functional groups that will react with one another under theconditions of blending to form the coating solution. In coatings createdby these methods, the HMG-CoA reductase inhibitors are preferablyphysically bound to the carrier but not chemically bound thereto.Accordingly, the chemical or molecular structure of the HMG-CoAreductase inhibitors is preferably unchanged when they are mixed withpolymers to form the coatings. Therefore, when the HMG-CoA reductaseinhibitors are released from these coatings, they remain in theirdesired active forms.

Liquid and low-melting polymers suitable for use as carriers in coatingcompositions according to the present invention may comprise abiodegradable polymer such as the biodegradable polymers discussedabove. Alternatively, the low-melting polymer may comprise a biostablepolymer, either alone or in combination with a biodegradable polymer.The term “biostable” is applied herein to any carrier, whether polymericor nonpolymeric, and whether liquid or solid, that does not break downin the body. In preferred embodiments, biostable polymers that arepreferred are biocompatible. Biostable low-melting polymers suitable foruse in the present invention include, but are not limited to, siliconeoils, prepolymers of polyurethanes, polyethylene glycol, polypropyleneglycol, polyethylene, polybutadiene, prepolymers of polyurethanes, andother biostable liquids known in the art.

In a preferred embodiment, the polymer used to form the coatingcomposition is low-melting polycaprolactone. Polycaprolactone isbiocompatible, and it has a low glass transition temperature, whichgives it flexibility and allows it to withstand the temperature changesstents often experience during their formation and use. For example,nitinol stents are preferably cooled to a temperature of about −50° C.so that they become flexible and can be compressed and fitted onto acatheter. A sheath placed over the stent (or another restraint such as awire binding the ends of the stent, prevents the stent from expanding asit is introduced into a patient's body at a higher temperature. Thesheath or other restraint is removed at the site of the stent's use, andthe stent re-expands to the size at which it is coated with acomposition that includes polycaprolactone. Polycaprolactone, unlikesome other stent coating materials, does not become brittle and crackthroughout these fluctuations in stent temperature and size. Preferably,the polycaprolactone has a molecular weight between about 300 and 2,000.The polymer may be a linear, branched, graft or dendramer polymer. Thepolymer may have different functional end groups but a functional groupthat is non-reactive with the bioactive component such as an alkyl groupis generally more preferred.

In one or more embodiments, the carrier may comprise more than onecompound. The coating composition may further comprise both a liquidcarrier and a solid carrier. In a still further aspect, the coatingcomposition may also comprise a liquid carrier having more than one typeof nonpolymeric or polymeric compound, and may further comprise both apolymeric material and a nonpolymeric material in the liquid carrier.The liquid carriers in the coating composition may be eitherbiodegradable or biostable. Biodegradable polymers which can be usedinclude those discussed above.

In a particularly preferred embodiment, the coating compositioncomprises a nonpolymeric liquid that remains a liquid after it isapplied to the stent and the stent is deployed within the body of apatient, i.e., the coating liquid has a melting point below bodytemperature (37° C.), preferably below 30° C., more preferably below 20°C., still more preferably below 10° C. The liquid is preferably aviscous liquid that adheres to the at least a portion of the externalsurface 28 of the stent 22 in sufficient quantity to deliver atherapeutically effective amount of the bioactive component uponexpansion in the body of the patient. In a preferred embodiment, thebioactive component is an HMG-CoA reductase inhibitor. Although theviscous liquid may be hydrophilic, in a preferred embodiment the viscousliquid is hydrophobic. Specifically, the carrier may comprise liquidVitamin E and derivatives thereof, such as vitamin E acetate and vitaminE succinate. In another preferred embodiment, the viscous, hydrophobicliquid comprises a C4-C36 fatty acid or mixtures of such fatty acids,such as oleic acid or stearic acid, by way of nonlimiting example. Inyet another preferred embodiment, the viscous, hydrophobic liquidcomprises an oil. Exemplary oils suitable for use in the presentinvention include peanut oil, cottonseed oil, mineral oil, low molecularweight (C4-C36), and other viscous organic compounds that behave as oilssuch as, by way of nonlimiting example, 1,2 octanediol and other lowmolecular weight alcohols and polyols. Olive oil has a viscosity of 84cP at 20° C. The viscosity of other materials is shown in Table 3 forreference purposes. TABLE 3 Viscosity of various materials at 20° C.Viscosity Substance Name (Centipoise) Water 1 Caster oil 986 Nylon resinmelt 100000 Diethyl ether 0.23 Olive oil 84 Benzene 0.65

In a preferred embodiment, the HMG-CoA reductase inhibitor used as abioactive component in the coating composition is cerivastatin.Cerivastatin is a very potent HMG-CoA reductase inhibitor. For example,when it is administered systemically, a therapeutic dose of cerivastatinis less than 1 mg per day, while other HMG-CoA reductase inhibitors mustbe administered in 50 mg doses. A thinner stent coating can be used ifcerivastatin is the chosen HMG-CoA reductase inhibitor instead of otherHMG-CoA reductase inhibitors because less of the bioactive coating isneeded. For example, a stent coating preferably has a thickness of about10-100 μm. If less drug and less carrier for that drug are required toinhibit restenosis, a stent coating having a thickness of 10-25 μm canbe used. A thinner stent coating may be preferred because it leaves moreof the arterial lumen open for blood flow. Thinner coatings are alsouseful in preserving sidebranch access in the case of coronary arteries.Sidebranches are small blood vessels that branch out from a coronaryartery and provide blood to some part of the heart.

Cerivastatin has other desirable properties, in addition to its abilityto inhibit the proliferation of smooth muscle cells that can contributeto restenosis. For example, cerivastatin has anti-thrombotic activity.Stents can often be sites of thrombus formation in the body because ofthe immunologically-triggered aggregation of different cell types andblood components at the site of a foreign object in the body. Includingcerivastatin in a stent coating may help prevent thrombus formation atthe site of the stent. Cerivastatin also promotes endothelialization, orthe repair of the endothelium 12 after it is damaged, such as by thedelivery and expansion of the stent in an artery or other body lumen. Itis contemplated that the endothelialization triggered by cerivastatincan help repair the endothelium, and thus reduce tears in theendothelium through which smooth muscle cells and other cell types canmigrate into the arterial lumen and proliferate, leading to restenosis.

As discussed above, other HMG-CoA reductase inhibitors may be used inthese stent coatings. For example, fluvastatin, simvastatin, lovastatin,atorvastatin, and pravastatin may be used. While these compounds areknown for their antihypercholesterolemic properties, it is believed thatthey may have other beneficial effects, such as restenosis inhibition orinhibition of smooth muscle cell proliferation, when they are deliveredin a localized manner, such as from a stent coating.

In one embodiment, the coating compositions described herein may includemore than one bioactive component, preferably more than onetype ofHMG-CoA reductase inhibitor. For example, a coating composition maycomprise cerivastatin and lovastatin. In other specific embodiments, thestent coatings described herein may comprise one or more drugs orbioactive compounds which inhibit restenosis and are not HMG-CoAreductase inhibitors. These drugs include, by way of nonlimitingexample, rapamycin, paclitaxel, and actinomycin D. It is contemplatedthat combining another drug with an HMG-CoA reductase inhibitor mayprovide a more effective coating composition for inhibiting restenosisthan a coating composition containing only one restenosis inhibitingagent.

Generally, the bioactive component is released from the stent bydiffusion of the bioactive component from the carrier. If the carriercomprises a biodegradable polymer, the bioactive component is preferablyreleased from the stent by the degradation of the polymer. A controlledrelease of the bioactive component from the coating can be achieved witha carrier comprising both a liquid and a solid through the relativelyrapid release of the diffusion of the bioactive component from theliquid and a slower release from the solid. In a still furtherembodiment, a highly controlled delivery of the bioactive component canbe achieved by a carrier comprising a liquid, a biodegradable(preferably solid) polymer, and a biostable (preferably solid) polymer.An initial release of the bioactive component from the liquid may befollowed by a slower release from the biodegradable solid, and a stillslower release from the biostable solid. The diffusion rate can bemonitored and the dose of the HMG-CoA reductase inhibitor can beadjusted to deliver the drug at a desired rate. In one embodiment, ahigher dose of a bioactive component can be delivered over a shortperiod of time by using a liquid that releases a known amount of theinhibitor within one to three days. In another embodiment, a higher doseof a bioactive component can be delivered over a short period of time byusing a nonpolymeric carrier such as vitamin E. In another embodiment,the bioactive component can be delivered via a biodegradable polymerthat degrades within a few days, e.g., low molecular weight polyglycolicacid, releasing the bioactive component by both diffusion and/or coatingdegradation. In another embodiment, the carrier may comprise anonpolymeric liquid and a biodegradable polymer that is a solid at roomtemperature and a liquid at body temperature.

Advantageously, the rate of release of a bioactive component from aliquid coating can be more easily predicted and is more consistent thanthe rate of release of a drug from other coatings in which the drug ischemically bound to the coating. With the coatings described herein, thebioactive component(s) are preferably physically released from thecoatings, and thus not dependent on a chemical step, cleavage orhydrolysis, the rate for which could vary in different patients as wellas within the same patient.

In at least certain embodiments the coating compositions of the presentinvention release their biologically active components in the body bothby diffusion of the bioactive compounds from the coatings and bydegradation of the coatings. For coating compositions that degradewithin a few days or weeks in the body, much of the release of thebiologically active components occurs in this time frame. Thistime-release feature is advantageous because it is believed that a highdose of a biologically active component, such as an anti-restenosiscompound or an antibiotic, delivered quickly can often be more effectivethan a lower dose delivered over a longer period of time. For example,bacterial infections are often treated with high doses of antibiotics assoon as the infection is detected. A high initial dose of antibioticsmay kill all of the bacteria, whereas a lower dose of antibioticsadministered over a longer period of time often results in the selectionfor, and survival of, bacteria that can survive in the presence of a lowdose of the drug. Similarly, it is contemplated that if a lowconcentration of a biologically active component, such as a restenosisinhibitor which inhibits smooth muscle cell proliferation, is releasedslowly from a stent, some smooth muscle cells will still be able toproliferate and partially occlude the artery. Then, when the supply ofthe biologically active component is exhausted, this small group ofsmooth muscle cells will continue to proliferate and block a largerpercentage of the arterial lumen. It is contemplated that this situationcan be avoided or minimized using coating compositions described herein,because it is believed that the liquid coatings will be removed from thestent and degraded within a few days or weeks, and thus deliver alocalized, high dose of a biologically active component in a shortperiod of time.

The liquid coating compositions described herein which are made frombiodegradable materials will degrade in the body and be removed from theangioplasty balloon or stent. When these coating compositions degrade,they typically degrade into their molecular subunits without creatingfragments that may irritate or damage the endothelium and lead torestenosis, possibly in areas remote from the site of stent deployment.Thus, these coating compositions provide safe, temporary coatings forstents. Also, the coatings typically provide a smooth surface forstents, which minimizes abrasion or tearing damage to the endothelium bystents during and after their implantation in the body. It iscontemplated that minimizing damage to the endothelium minimizes thelikelihood of the development of restenosis. The coating compositionsmay also protect the stent itself from chemical or physical damage inthe body

The coatings of the present invention are suitable for use on any knowncardiovascular stent such as, e.g., the Palmaz stent disclosed in U.S.Pat. Nos. 4,733,665 and 4,739,762. Other stents may also be used.Notwithstanding the foregoing, in a preferred embodiment, the coatingcompositions described herein are used on stents having struts, andfurther including a surface enhancing feature such as capillaries,grooves or channels in the struts, in which the coating composition cancollect and be retained by surface tension.

The coating compositions described herein preferably remain on a stent,partially or in substantial part, after the stent has been introduced tothe body, for at least several days and more preferably for severalweeks. In one or more specific embodiments, the coating composition is asolid until it is placed in the body together with the stent, at whichtime it begins to melt to form a liquid, e.g., at 37° C. Morepreferably, the coating composition does not melt immediately uponinsertion into the body, but melts upon reaching the site of its use.

As discussed above, one type of medical device suitable for use inconnection with coatings of the present invention is an angioplastyballoon. The liquid coating compositions described herein preferablyremain substantially intact on an angioplasty balloon during theinsertion of the balloon through the body to the site of its use. Someof the coating composition will be transferred from the balloon to thehydrophobic plaque at the occluded site in the artery when the balloonis inflated at the site of an artery blockage. This is advantageousbecause the biologically active component in the coating compositionwill be directly transferred with the carrier onto the plaque. In thismanner, the biologically active component can be delivered directly toits desired site of use. In a preferred embodiment, the coatingcompositions are hydrophobic. When hydrophobic coating compositions areused, they tend to dissolve faster than non-hydrophobic coatingcompositions after contacting the hydrophobic plaque and, thus, morereadily release the biologically active component.

The coating composition comprising the carrier and the bioactivecomponent can be applied to a stent in a number of different ways.Preferably, a stent is coated in its expanded form so that a sufficientamount of coating will be applied to completely coat the expanded stent.In a preferred embodiment, the coating composition is at least initiallyapplied to the stent as a liquid. Spraying the stent with the liquidcarrier results in a coating of uniform thickness on the struts of thestent. Where the coating composition comprises a polymer, the polymer ispreferably dissolved in a suitable solvent to form a polymer solutionand the stent is sprayed with the solution to provide the coating.Alternatively, the polymer solution may be painted on the stent orapplied by other means known in the art, such as electrodeposition,dipping, casting or molding. In one embodiment, the stent may be dipcoated or immersed in the solution, such that the solution completelycoats the struts of the stent. In each of these coating applications,the entirety of both the outer and inner surfaces of the stent arepreferably coated, although only portions of either or both surfaces maybe coated in alternative embodiments. In one embodiment, excess coatingcomposition is allowed to drain from the stent. In another embodiment,the solvent may then be dried to yield a solid coating compositionhaving a melting point of 50° C. or less, preferably at body temperatureor less. In a preferred embodiment, the stent is dried at from 20° C. to30° C., preferably at room temperature, for a period of time sufficientto remove the solvent. The drying temperature should not be so high asto cause the polymer to react chemically with the HMG-CoA reductaseinhibitor.

Generally, coating a stent by completely coating the struts of the stentis preferred. Complete coating typically provides uniform distributionof a drug along the surfaces of the stent. The top coating may be usedto control the diffusion of the drug from the stent. The thickness ofthe coating is preferably 0.1 microns to 2 mm, more preferably from 1 to100 microns, even more preferably from 1 to 25 microns. However, toprovide additional coating to effect release of higher doses of thebioactive component, grooves, capillaries, channels or other depressionsin the surface of the stent or struts may be provided to increase thesurface area and thereby provide sites of enhanced adhesion of thecoating.

As used herein, the term “solvent” is defined according to its broadestrecognized definition and includes any material into which the carrierand/or the bioactive agent can dissolve, fully or partially, at roomtemperature or from 20° C. to 50° C. Methylene chloride is a preferredsolvent for polymeric compositions. Methylene chloride's low boilingpoint facilitates removal from the polymer and the HMG-CoA reductaseinhibitor at ambient temperatures by evaporation. However, it iscontemplated that virtually any organic solvent that dissolves thepolymer can be used. Solvents that can cause corrosion, such as highlyacidic or basic aqueous solutions, are not preferred. Organic solventsthat are biocompatible, have low boiling points and high flash points,are preferred. Other solvents that may be used include chloroform,toluene, cyclohexane, acetone, methylethyl ketone, ethyl formate, ethylacetate, acetonitrile, n-methyl pyrrolidinone, dimethyl sulfoxide,n,n-dimethylacetamide, n,n-dimethyl formamide, ethanol, methanol, aceticacid, and supercritical carbon dioxide.

In another aspect, the invention can include a method of coating astent. A specific embodiment of the method includes providing a stent,providing a coating composition comprising a biologically activecomponent and a carrier component that has a melting point of about 50°C. or less, more preferably about 40° C. or less, most preferably bodytemperature (37° C.) or less, and applying the coating composition tothe stent. In another embodiment, the invention includes a method thatcomprises providing a coating composition that includes a biologicallyactive component and a liquid carrier component which has a viscosity offrom about 0.1 to about 15000 cP, and applying the coating compositionto the stent.

In a specific embodiment, the method of coating a stent comprisesproviding a stent, providing a coating composition comprising a blend ofa substantially unreacted bioactive component and a polymeric ornonpolymeric carrier having a melting point of about 50° C. or less, andapplying the coating composition to the stent. Providing the coatingcomposition may comprise mixing the bioactive component and anonpolymeric liquid carrier. In one embodiment, the nonpolymeric liquidcarrier comprises a C-6 to C-18 fatty acid, such as oleic acid orstearic acid. In another embodiment, the liquid carrier comprises aliquid selected from the group consisting of vitamin E, peanut oil,cottonseed oil, and mineral oil. In another embodiment, providing thecoating composition may comprise mixing the bioactive component and apolymeric liquid carrier. In a further embodiment, providing the coatingcomposition may include mixing an HMG-CoA reductase inhibitor, alow-melting polymer, and a solvent under conditions such that theHMG-CoA reductase inhibitor does not chemically react with the polymer,or does not react to any substantial extent, applying the mixture to thestent, and removing the solvent. Providing the coating composition mayalso include mixing the HMG-CoA reductase inhibitor, a polymer, and asolvent at a temperature of from about 20° C. to about 30° C.,preferably at about 22° C. In another embodiment, providing a coatingcomposition may include providing a solid coating comprising an HMG-CoAreductase inhibitor and a polymer.

In one or more specific embodiments, the invention can include atreatment method, comprising deploying a coated stent into a body lumenof a patient, the coated stent comprising a stent and a coatingcomposition that comprises a carrier component and a bioactivecomponent, the biodegradable component having a melting point of about50° C. or less. In a preferred embodiment, the carrier is biodegradable,although biostable carriers may also be used. In other specificembodiments, the coated stent comprises a stent and a coatingcomposition that includes a carrier component and a bioactive component,the carrier having a viscosity of from about 0.1 to about 15000. In yetanother specific embodiment, the coated stent comprises a stent and acoating composition that includes a biodegradable carrier component anda bioactive component, and the carrier is in a solid state outside of ahuman body and a liquid inside of a human body.

In another aspect, the invention can include a treatment methodcomprising attaching a stent to a catheter, applying to the catheter andthe stent a coating composition comprising a biodegradable carriercomponent having a melting point of about 50° C. or less and a bioactive component, and deploying the coated stent into a body lumen of apatient.

In another aspect, the invention includes a method of treating anoccluded artery comprising providing a stent, providing a coatingcomposition comprising a low-melting nonpolymeric or polymeric carrierand a bioactive component in an amount effective to prevent orsubstantially reduce restenosis, applying the coating composition to thestent, and deploying the stent in the occluded artery at the site ofocclusion. Providing a coating composition may comprise dissolving orsuspending in a nonpolymeric liquid or low-melting carrier an amount ofan HMG-CoA reductase inhibitor effective to prevent or substantiallyreduce restenosis. In another embodiment, providing a coatingcomposition may comprise dissolving in a polymeric liquid or low-meltingcarrier an amount of an HMG-CoA reductase inhibitor effective to preventor substantially reduce restenosis in an occluded vascular lumen. Wherea polymeric carrier is provided, the HMG-CoA reductase inhibitor may bephysically bound to the polymer, chemically bound to the polymer, orboth. The coating composition may be a solution that comprises theHMG-CoA reductase inhibitor, the polymer, and a solvent. The solvent maybe removed by, e.g., drying the stent or other methods known in the art.In another embodiment, the coating composition may comprise the HMG-CoAreductase inhibitor and a polymer having a melting point between 30° C.and 50° C., and applying the coating composition to the stent maycomprise melting the coating composition, spraying the melted coating onthe stent, and allowing the coating to solidify. The coating compositionmay include an amount of the HMG-CoA reductase inhibitor that istherapeutically effective for inhibiting regrowth of plaque orinhibiting restenosis. More particularly, the coating composition maycomprise from about 1 wt % to about 50 wt % HMG-CoA reductase inhibitor,based on the total weight of the coating composition.

In another aspect, the invention can include a method of treatingrestenosis, comprising inserting a coated stent into a body lumen, thecoated stent comprising a stent and a coating composition comprising asubstantially unreacted HMG-CoA reductase inhibitor and a low-melting,nonpolymeric or polymeric carrier, which may be a liquid or a solid. Inone embodiment, the coated stent releases the HMG-CoA reductaseinhibitor in an amount sufficient to inhibit the proliferation of smoothmuscle cells. In another embodiment, the coated stent releases theHMG-CoA reductase inhibitor in an amount sufficient to inhibitrestenosis.

In another aspect, the invention may comprise a method of localizeddelivery of an HMG-CoA reductase inhibitor, comprising inserting acoated stent into a body lumen, the coated stent comprising a stent anda coating composition comprising a substantially unreacted HMG-CoAreductase inhibitor and a low-melting polymeric or nonpolymeric carrier.In one embodiment, the coated stent releases the HMG-CoA reductaseinhibitor in an amount effective to inhibit the proliferation of smoothmuscle cells. In another embodiment, the coated stent releases theHMG-CoA reductase inhibitor in an amount effective to inhibitrestenosis.

In another aspect, the invention can include a coated stent, comprisinga stent and a coating composition comprising a biologically activecomponent and a biodegradable carrier component which may have a meltingpoint of about 50° C. or less, and a catheter which can be coupled tothe coated stent to form a treatment assembly.

In accordance with methods and compositions described herein, restenosismay be prevented or lessened using localized delivery of HMG-CoAreductase inhibitors from a liquid or low-melting carrier coupled to astent placed in a body lumen. Preferably, metal stents are coated with abiocompatible coating composition comprising a carrier and an effectiveamount of an HMG-CoA reductase inhibitor. The coated stent can bedeployed during any conventional percutaneous transluminal coronaryangioplasty (PTCA) procedure. Controlled delivery from a stent of theactive HMG-CoA reductase inhibitor, using a coating such as thatdescribed herein, in an effective amount, can inhibit the regrowth ofplaque and prevent restenosis. While the stents shown and described inthe various embodiments are vascular stents, any type of stent suitablefor deployment in a body lumen of a patient may be used with thecoatings described herein.

In certain specific embodiments of the coated stents and the methodsdescribed above, the coating compositions used may include more than oneHMG-CoA reductase inhibitor or a restenosis inhibitor which is not anHMG-CoA reductase inhibitor. Preferably, these components are releasedfrom a stent in an amount effective to inhibit restenosis.

EXAMPLES

The following examples are included to demonstrate differentillustrative embodiments or versions of the invention. However, thoseskilled in the art should, in light of the present disclosure,appreciate that many changes can be made in the specific embodimentswhich are disclosed and still obtain a like or similar result withoutdeparting from the spirit and scope of the invention.

Coronary stents were provided by Baylor Medical School and SulzerIntratherapeutics. Poly(lactic acid)-co-poly(glycolic acid) (PLGA)polymer was purchased from Boehringer Ingelheim. Methylene chloride waspurchased from Aldrich. Sulzer Carbomedics, Inc. provided medical gradesilicone rubber.

Example 1

100 mg EVA (ethylene-vinyl acetate) polymer and 10 mg of cerivastatinwere dissolved in 10 ml methylene chloride solution at room temperature.The solution was poured onto a glass plate and the solvent was allowedto evaporate for 12-24 hours. After almost complete removal of thesolvent, the cerivastatin-loaded EVA film was removed from the glassplate and was cut to 1.5 cm by 1.5 cm size. The film was mounted on aPalmaz-Schatz coronary endovascular stent. Control EVA films wereprepared in the following manner: 100 mg EVA polymer was dissolved in 10ml methylene chloride solution at room temperature. The solution waspoured onto a glass plate and the solvent was allowed to evaporate for12-24 hours. After almost complete removal of the solvent, the controlEVA film was removed from the glass plate and was cut to 1.5 cm by 1.5cm size. The control film was mounted on a Palmaz-Schatz coronaryendovascular stent. Release profiles were obtained for the coatedstents.

Example 2

A 10% w/w solution of cerivastatin in vitamin E was created by thefollowing method. Four (4) mg of cerivastatin was dissolved in onehundred (100) μl of methylene chloride. This solution was added to 36 mgof liquid vitamin E and mixed manually by stirring. The solution wasallowed to stand at room temperature for one hour to enable themethylene chloride to evaporate from the solution. The resultingcerivastatin/vitamin E mixture was used to coat three “Protégé” stentsby simple surface application. Approximately 10-12 mg of vitamin E anddrug was deposited on each stent.

Example 3

A coated stent prepared according to Examples 1 and 2 is immersed in anEppendorf tube containing 1 ml phosphate buffered saline (PBS) andincubated on a rotator in a 37° C. oven. Buffer exchanges are performedat 1, 2, and 4 days following immersion in PBS. Collected samples areassayed for rifampin concentration using a UV-VIS spectrophotometer.

Example 4

A 50 ml round bottom flask with a Teflon coated magnetic stirrer isflame dried under repeated cycles of vacuum and dry nitrogen. Two (2) gtrimethylol propane, 11.68 g D,L-lactide, and 0.20 mg stannous octoateare charged to the flask. The flask is then heated to 165° C. for 16hours and then cooled. The liquid product is dissolved in. 30 ml tolueneand precipitated in large excess cold hexane. The precipitated polymer,which is a liquid at room temperature, is isolated and can be used incoating stents.

Example 5

Polycaprolactone diol (MW 2000) (PCL 2000) is purchased from Aldrich.This polymer melts at approximately 60-70° C., depending upon itsthermal (cooling) history and the degree of crystallinity in the bulkpolymer. This polymer is insoluble in water.

Example 6

Polycaprolactone triol (MW 300) (PCL 300) is purchased from Aldrich andused as received. This polymer is liquid at room temperature and isimmiscible with water.

Example 7

One (1) g of PCL 300, a liquid at room temperature, and 50 mg of PCL2000, a solid at room temperature, are mixed to obtain a viscous mixturewhich is liquid at room temperature. The viscosity of the mixture isgreater than the viscosity of PCL 300.

Example 8

One (1) g PCL 300 (See Example 6) and 10 mg rifampin are added to a 2 mlglass vial. A 7×20 mm metal stent (Lot R0036203, Sulzer IntraTherapeutics) is added to the vial. The excess liquid on the surface ofthe stent is removed. The coated stent is then sterilized using ethyleneoxide, compressed, and mounted on a balloon angioplasty catheter. It isthen deployed at a diseased site in an artery using standard balloonangioplasty techniques and implanted at the site of reduced blood flowor obstruction of the artery. The hydrophobic liquid layer on the stentreleases the drug in a controlled fashion.

Example 9

One (1) g PCL 300 (see Example 6) and 10 mg rifampin are added to a 2 mlglass vial. A paint brush is used to coat an angioplasty balloon surfacewith the PCL 300-rifampin mixture. The balloon is sterilized usingethylene oxide, compressed, and mounted on the balloon angioplastycatheter. It is then deployed at a diseased site in a coronary arteryusing standard balloon angioplasty technique. The coated balloon isexpanded at the site of reduced blood flow or obstruction in the artery.The contact of the balloon surface with the arterial lumen walltransfers a portion of the liquid coating onto the wall surface as wellas onto the material obstructing the arterial lumen. The hydrophobicliquid layer is transferred onto the lumen walls and onto theobstructing material, delivering the bioactive compound in a controlledmanner.

Controlled release studies were done to determine the integrity andactivity of cerivastatin released from stents coated with a solidpolymer carrier and cerivastatin, and a vitamin E liquid carrier andcerivistatin. Stents coated according to the process of Examples 1 and 2were immersed in an Eppendorf tube containing 1 ml phosphate bufferedsaline (PBS) and incubated on a rotator in a 37° C. oven. Bufferexchanges were performed at 1, 2, and 4 days following immersion in PBS.Collected samples were assayed for the spectral characteristics ofcerivastatin using a UV-VIS spectrophotometer. Cerivastatin releasedfrom an EVA and cerivastatin coated stent such as the stent of Example 1and pure cerivistatin in deionized water had almost identical UV-VISspectra, as shown in FIG. 4, suggesting that the cerivastatin releasedfrom the stent was unaltered and thus remained biologically active.

The release of cerivistatin from stents coated according to the processof Example 1 was monitored over 7 days, as shown in FIG. 5. An EVA andcerivastatin coated stent such as the stent of Example I released >20μg/ml cerivastatin per day (see FIG. 5), which is significantly higherthan the 0.5 μg/ml concentration needed to inhibit proliferation ofsmooth muscle cells. Thus, stents produced according to this inventionrelease a sufficient amount of cerivastatin to inhibit the proliferationof smooth muscle cells which occurs during restenosis.

The release of cerivastatin from stents coated with vitamin E accordingto the process of Example 2 was monitored over 11 days, as shown in FIG.6. A liquid vitamin E and cerivastatin coated stent such as the stentsof Example 2 released >20 μg/ml cerivastatin per day.

While the foregoing is directed to embodiments of the present invention,other and further embodiments of the invention may be devised withoutdeparting from the basic scope thereof, and the scope thereof isdetermined by the claims that follow, including equivalents.

1. A coated stent comprising a stent and a coating compositioncomprising a biologically active component and a biodegradable carriercomponent, the biodegradable carrier having a melting point of about 50°C. or less.